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FP7

UBIFLU — Result In Brief

Project ID: 321703
Funded under: FP7-PEOPLE
Country: Switzerland
Domain: Health, Fundamental Research

Host targets for novel influenza drugs

Prevention and treatment of influenza with vaccines and antivirals lacks efficiency due to emergence of novel viral strains as well as drug resistance. There is a need for antivirals that minimise the development of drug-resistant strains.
Host targets for novel influenza drugs
The influenza virus infection process relies on host cell functions. One way to minimise the development of resistance to the antivirals is to target the host cell proteins required for virus replication. The EU-funded UBIFLU project investigated proteins that have been identified in genome-wide siRNA screens as potential host factors required for influenza virus replication.

Reversible posttranslational modification of proteins provides cells with a mechanism to modulate functionality in response to many stimuli, including pathogen invasion. Ubiquitin and ubiquitin-like protein modifiers are central players in mediating the host innate immune response to infection. The small ubiquitin-like modifiers (SUMOs) are proteins that are predominantly located in the cell nucleus and reversibly attached to lysine residues in target proteins. Influenza viruses are atypical RNA viruses that replicate in host-cell nuclei and encode multiple proteins that become SUMO-modified during infection to regulate their trafficking and function.

Researchers established that influenza virus infection resulted in the dramatic redistribution of intra-nuclear SUMOs along with an increase in SUMO conjugates. Curiously, this increase in SUMO-modification was dependent on virus genome replication and protein synthesis, but independent of canonical virus-activated stress pathways.

The study also discovered that viral RNA polymerase activity is a major trigger for SUMO-modification during influenza infection. Application of the affinity proteomics approach allowed the system-wide identification of the SUMO1- and SUMO2- modified proteome in human lung epithelial cells. Analysed in combination with the results from the large-scale shRNA-depletion screening, the data suggested that influenza virus infection re-targets SUMO modifications to several of the host factors that modulate virus replication.

Overall, the project results on SUMO post-translational modifications during influenza infection established a new framework for understanding the way in which the host-cell nucleus is changed by the virus. Further investigation of the molecular basis of the response and the proteins involved will be essential to develop novel anti-influenza therapeutic strategies.

Related information

Subjects

Life Sciences

Keywords

Influenza, drug resistance, host cell proteins, UBIFLU, SUMO-modification
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